Cognitive deficits as well as positive and negative symptoms in schizophrenia may arise from abnormalities[unreadable] in very basic processes of detecting and encoding stimuli in appropriate neural circuitry. Those processes[unreadable] can be monitored with event-related potentials (ERPs), EEG oscillations and fMRI activation. Abnormalities[unreadable] have been reported repeatedly in schizophrenia in multiple auditory cortical ERPs and in theta and gamma[unreadable] EEG rhythms associated with deviance and novelty detection, as well as with encoding and retrieval of[unreadable] episodic and working memory. As described in Subprojects 0001 and 0003, our CCNMD has found that in schizophrenia[unreadable] gamma oscillatory abnormalities correlate with abnormal fMRI BOLD responses, including those in superior[unreadable] temporal gyrus and hippocampus. The microcircuits generating gamma and theta rhythms in neocortex and[unreadable] hippocampus have been elucidated in recent years. In both brain regions, the microcircuits are similar and[unreadable] consist of glutamatergic projection neurons reciprocally connected with one or more types of GABAergic[unreadable] interneurons. We propose that in schizophrenia hypofunction of glutamatergic input to GABAergic[unreadable] interneurons occurs in theta and gamma microcircuits with consequent GABAergic hypofunction leading to[unreadable] abnormal oscillations in the circuits.[unreadable] Our studies have identified factors in schizophrenia that could lead to glutamatergic and GABAergic[unreadable] dysfunction in hippocampal and cortical brain regions, including abnormal dysbindin expression and[unreadable] abnormal activation of NMDA receptors and the neuregulin 1-erbB4 signaling pathway. Subproject 0007 will test[unreadable] hypotheses related to these findings and potential consequences for glutamatergic-GABAergic[unreadable] neurotransmission. Aim 1 will examine whether or not presynaptic factors that contribute to glutamatergic[unreadable] function of theta and gamma microcircuits are abnormal in schizophrenia and a dysbindin mutant mouse[unreadable] (sandy). Aim 2 will use a novel neurochemical stimulation paradigm in human postmortem tissue and a Gsa[unreadable] overexpressing mouse to examine NMDA receptor function and NMDAR-dopamine receptor interactions that[unreadable] may contribute to theta and gamma microcircuit dysfunction in schizophrenia. Aim 3 will examine whether[unreadable] markers of GABAergic transmission are in fact altered in the gamma and theta microcircuits in that disorder.